scholarly journals MLL1 is required for maintenance of intestinal stem cells and the expression of the cell adhesion molecule JAML

2020 ◽  
Author(s):  
Neha Goveas ◽  
Claudia Waskow ◽  
Kathrin Arndt ◽  
Julian Heuberger ◽  
Qinyu Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adhesion Molecule ◽  
Adult Stem Cells ◽  
Paneth Cells ◽  
Intestinal Stem Cells ◽  
Epigenetic Mark ◽  
Hematopoietic Stem ◽  
Histone 3 ◽  
H3k4 Methyltransferases

AbstractEpigenetic control is crucial for lineage-specific gene expression that creates cellular identity during mammalian development and in adult organism. Histone 3 lysine 4 methylation (H3K4) is a universal epigenetic mark. Mixed lineage leukemia (MLL1) is the founding member of the mammalian family of H3K4 methyltransferases. It was originally discovered as the main gene mutated in early onset leukemias and then found to be required for hematopoietic stem cell development and maintenance. However, the roles of MLL1 in non-hematopoietic tissues remain largely unexplored. To bypass hematopoietic lethality, we used bone marrow transplantation and conditional mutagenesis to discover that the most overt phenotype in Mll1-mutant mice is intestinal failure. Loss of MLL1 is accompanied by a differentiation bias towards the secretory lineage with increased numbers of goblet cells. MLL1 is expressed in intestinal stem cells (ISCs) and transit amplifying (TA) cells but at reduced levels in Paneth cells and not in the villus. MLL1 is required for the maintenance of intestinal stem cells (ISCs) and proliferation in the crypt. Transcriptome analysis implicate MLL1-dependent expression in ISCs of several transcription factors including Pitx2, Gata4, Foxa1 and Onecut2, and also a cell adhesion molecule, Jaml. Reactive transcriptome changes in Paneth cells and organoids imply that JAML plays a key role in the crypt stem cell niche. All known postnatal functions of MLL1 relate to stem cell maintenance and lineage decisions thereby highlighting the suggestion that MLL1 is a master stem cell regulator.Author SummaryThe ability of adult stem cells to produce functional progenies through differentiation is critical to maintain function and integrity of organs. A fundamental challenge is to identify factors that control the transition from self-renewal to the differentiated state. Epigenetic factors amongst others can fullfill such a role. Methylation of histone 3 on lysine 4 (H3K4) is a posttranslational epigenetic modification that is associated with actively transcribed genes. In mammals, this epigenetic mark is catalyzed by one of six H3K4 methyltransferases, including the founding member of the family, MLL1. MLL1 is important for the precise functioning of the hematopoietic stem cell compartment. This raises the possibility of similar functions in other adult stem cell compartments. Due to its intense self-renewal kinetics and its simple repetitive architecture, the intestinal epithelium serves as a prime model for studying adult stem cells. We demonstrate that MLL1 controls intestinal stem cell proliferation and differentiation. Additionally, transcriptome analysis suggests a pertubation in the close interaction between intestinal stem cells and neighbouring Paneth cells through loss of junction adhesion molecule like (JAML). Our work sheds new light on the function of MLL1 for the control of intestinal stem cell identity.

scholarly journals MLL1 is required for maintenance of intestinal stem cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009250
Author(s):  
Neha Goveas ◽  
Claudia Waskow ◽  
Kathrin Arndt ◽  
Julian Heuberger ◽  
Qinyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Stress Responses ◽  
Expression Patterns ◽  
Paneth Cells ◽  
Intestinal Stem Cells ◽  
Causative Mutation ◽  
Hematopoietic Stem ◽  
Conditional Mutagenesis

Epigenetic mechanisms are gatekeepers for the gene expression patterns that establish and maintain cellular identity in mammalian development, stem cells and adult homeostasis. Amongst many epigenetic marks, methylation of histone 3 lysine 4 (H3K4) is one of the most widely conserved and occupies a central position in gene expression. Mixed lineage leukemia 1 (MLL1/KMT2A) is the founding mammalian H3K4 methyltransferase. It was discovered as the causative mutation in early onset leukemia and subsequently found to be required for the establishment of definitive hematopoiesis and the maintenance of adult hematopoietic stem cells. Despite wide expression, the roles of MLL1 in non-hematopoietic tissues remain largely unexplored. To bypass hematopoietic lethality, we used bone marrow transplantation and conditional mutagenesis to discover that the most overt phenotype in adult Mll1-mutant mice is intestinal failure. MLL1 is expressed in intestinal stem cells (ISCs) and transit amplifying (TA) cells but not in the villus. Loss of MLL1 is accompanied by loss of ISCs and a differentiation bias towards the secretory lineage with increased numbers and enlargement of goblet cells. Expression profiling of sorted ISCs revealed that MLL1 is required to promote expression of several definitive intestinal transcription factors including Pitx1, Pitx2, Foxa1, Gata4, Zfp503 and Onecut2, as well as the H3K27me3 binder, Bahcc1. These results were recapitulated using conditional mutagenesis in intestinal organoids. The stem cell niche in the crypt includes ISCs in close association with Paneth cells. Loss of MLL1 from ISCs promoted transcriptional changes in Paneth cells involving metabolic and stress responses. Here we add ISCs to the MLL1 repertoire and observe that all known functions of MLL1 relate to the properties of somatic stem cells, thereby highlighting the suggestion that MLL1 is a master somatic stem cell regulator.

JMJD3 Plays Essential Roles in the Maintenance of Hematopoietic Stem Cells and Leukemic Stem Cells through the Regulation of p16INK4a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2653-2653 ◽  
Author(s):  
Yuichiro Nakata ◽  
Norimasa Yamasaki ◽  
Takeshi Ueda ◽  
Kenichiro Ikeda ◽  
Akiko Nagamachi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Epigenetic Mark ◽  
M2 Macrophage ◽  
Leukemic Stem Cells ◽  
Cell Potential ◽  
Hematopoietic Stem

Abstract Hematopoiesis is a complex process that involves the interplay between lineage-specific transcription and epigenetic regulation, including histone modifications. Tri-methylation of histone H3 at Lys27 (H3K27me3) is an epigenetic mark for transcriptional repression. Jumonji domain-containing 3 (JMJD3) acts as a histone demethylase for H3K27 and contributes to various cellular processes including senescence and differentiation through transcriptional regulation. In the hematopoietic system, JMJD3 has been reported to be required for M2 macrophage development and terminal thymocyte differentiation. However, the roles of JMJD3 in normal hematopoiesis and leukemogenesis are still largely elusive. To address this issue, we generated pIpC-inducible Jmjd3 conditional KO (cKO) mice. Jmjd3-deficient (Jmjd3Δ/Δ) mice grew healthy and did not show obvious hematopoietic abnormalities, except a slight decrease of myeloid cells. To investigate the role of JMJD3in hematopoietic stem cell (HSC) function, a competitive repopulation assay was performed using control and Jmjd3Δ/Δ HSCs. The results showed that the chimerism of Jmjd3Δ/Δ cells was significantly decreased compared with that of control cells in all the hematopoietic lineages, indicating that JMJD3 is essential for long-term repopulating ability of HSCs. To further investigate the effect of Jmjd3 deletion in leukemogenesis, c-kit+ bone marrow (BM) cells from control and Jmjd3 cKO mice were transduced with MLL-AF9 fusion protein that rapidly induces acute leukemia. L-GMPs (the fraction containing leukemic stem cells (LSCs)) were sorted from MLL-AF9-transduced BM cells and subjected to colony replating and bone marrow transplantation (BMT) assays. In contrast control L-GMPs that continued to form colonies after multiple rounds of replating, Jmjd3Δ/Δ L-GMPs ceased to proliferate after third rounds of replating. In addition, recipients transplanted with Jmjd3Δ/Δ L-GMPs exhibited a significant delay in the onset of leukemia compared with those transplanted with controlL-GMPs. These results indicate that JMJD3 plays essential roles in maintaining stem cell properties not only in normal HSCs but also in LSCs. We next investigated underlying molecular mechanisms. Previous studies demonstrated the INK4a/ARF locus, a key executor of cellular senescence, is regulated by JMJD3. Thus, we examined whether JMJD3 regulates INK4a/ARF locus in hematopoietic cells under proliferative and oncogenic stresses. We found that enforced expression of Jmjd3 in in vitro-cultured and cytokine-stimulated hematopoietic stem-progenitor cells (HSPCs) significantly upregulated the expression of p16INK4a compared with control cells. In addition, transformation of HSPCs by MLL-AF9 induced expression of Jmjd3, but not other H3K27me3-related genes, such as Utx and EZH2, which was accompanied by the upregulation of p16INK4a. In contrast, no obvious expressional change was observed in p19ARF in both cases. In Jmjd3Δ/Δ HSPCs, no upregulation of p16INK4a was detected in HSPCs by cytokine-induced proliferation or MLL-AF9-induced transformation, where H3K27me3 was tightly associated with promoter region of p16INK4a locus. These results strongly suggest that proliferative and oncogenic stresses induces the expression of Jmjd3 in HSPCs, which subsequently upregulates p16INK4a through demethylating H3K27me3 on the p16INK4a promoter and consequently maintains stem cell potential by inhibiting excessive entry into cell cycle. Deficiency of Jmjd3 fails upregulation of p16INK4a, which induces continuous and excessive cell proliferation and finally causes exhaustion of stem cell pool. In conclusion, we propose the idea that JMJD3-p16INK4a axis plays essential roles in maintaining HSC and LSC pool size under proliferative and oncogenic stresses. Disclosures No relevant conflicts of interest to declare.

scholarly journals Two anatomically distinct niches regulate stem cell activity

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2174-2181 ◽  
Author(s):  
Hideo Ema ◽  
Toshio Suda
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Cell Activity ◽  
Cell Types ◽  
Cell Number ◽  
Cell Regulation ◽  
Hematopoietic Stem ◽  
Stem Cell Regulation ◽  
Cellular Components

Abstract The niche microenvironment controls stem cell number, fate, and behavior. The bone marrow, intestine, and skin are organs with highly regenerative potential, and all produce a large number of mature cells daily. Here, focusing on adult stem cells in these organs, we compare the structures and cellular components of their niches and the factors they produce. We then define the niche as a functional unit for stem cell regulation. For example, the niche possibly maintains quiescence and regulates fate in stem cells. Moreover, we discuss our hypothesis that many stem cell types are regulated by both specialized and nonspecialized niches, although hematopoietic stem cells, as an exception, are regulated by a nonspecialized niche only. The specialized niche is composed of 1 or a few types of cells lying on the basement membrane in the epithelium. The nonspecialized niche is composed of various types of cells widely distributed in mesenchymal tissues. We propose that the specialized niche plays a role in local regulation of stem cells, whereas the nonspecialized niche plays a role in relatively broad regional or systemic regulation. Further work will verify this dual-niche model to understand mechanisms underlying stem cell regulation.

High Mobility Group A1 Chromatin Remodeling Protein Regulates Self-Renewal, Niche Formation, and Regenerative Function in Adult Stem Cells through Wnt/β-Catenin Signaling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2647-2647 ◽  
Author(s):  
Linda Resar ◽  
Lingling Xian ◽  
Tait Huso ◽  
Amy Belton ◽  
Leslie Cope ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chromatin Remodeling ◽  
Adult Stem Cells ◽  
Cell Function ◽  
High Mobility ◽  
Transcriptional Networks ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract Introduction: Nuclear chromatin structure is a key determinant of stem cell function and cell fate, although factors that regulate this are only beginning to emerge. While High Mobility Group A1(HMGA1) chromatin remodeling proteins are among the most abundant, nonhistone chromatin binding proteins in adult stem cells (ASCs), their role in this setting has been unknown. HMGA1/2 proteins modulate gene expression by binding to DNA, bending chromatin, and recruiting transcription factor complexes to enhancers throughout the genome. The HMGA1 gene is highly expressed during embryogenesis with low or undetectable levels in mature, differentiated tissues. In cancer, HMGA1 re-expression occurs through oncogenic transcription factors, other epigenetic alterations, or in rare cases, chromosomal translocation events. Importantly, HMGA1 levels correlate with adverse clinical outcomes in diverse malignancies. We previously reported that Hmga1 transgenic mice develop leukemic transformation by inducing transcriptional networks involved in stem cell function and cell cycle progression. Methods: To elucidate the role of Hmga1 in normal development and ASCs in vivo, we generated mouse models with transgenic overexpression or deletion of Hmga1. To define the function of Hmga1 in adult stem cells (ASCs), we used gain-of-function (overexpression) and loss-of-function (silencing or genetic deletion) approaches in human and murine intestinal stem cells (ISCs) and hematopoietic stem and progenitor cells. Results:Transgenic mice overexpressing Hmga1 in ISCs develop hyperproliferation, aberrant crypt formation, and polyposis in the intestinal epithelium by expanding the ISC and niche compartments. Hmga1 enhances self-renewal in ISCs by amplifying Wnt/β-catenin signaling, inducing genes that encode both Wnt agonist receptors and downstream Wnt effectors. Surprisingly, Hmga1 also "builds" an epithelial niche by directly up-regulating Sox9 to induce Paneth cell differentiation. Paneth cells constitute the epithelial ISC niche by secreting Wnt agonists. This is the first example of Hmga1 fostering terminal differentiation to establish a stem cell niche. In human intestine, HMGA1 and SOX9 are highly correlated, and both become up-regulated in colorectal cancer. Human CD34+ cells engineered to overexpress Hmga1 expand more efficiently, while those with Hmga1 deficiency have defective proliferation and colony forming capability. Both colony number and size were decreased, and differentiation was skewed towards myeloid lineages. In mice, Hmga1 deletion causes partial embryonic lethality; over 50% of expected offspring die before mid-gestation. Those that survive develop premature aging phenotypes with early kyphosis, decreased bone density, grip strength, gait velocity, and hearing deficits. Knock-out mice also have early thymic aplasia, decreased numbers of early T-cell precursors, as well as decreased B-cell differentiation. Long-term (LT)-hematopoietic stem cells were decreased and preliminary data suggests aberrant regenerative function in serial, competitive transplant experiments.Preliminary ChIP-seq and gene expression studies in CD34+ cells suggest that Hmga1 regulates transcriptional networks involved in Wnt, JAK-STAT, and PI3K signaling. Conclusions:Our results in ASCs reveal a novel role for Hmga1 in tissue homeostasis by inducing pathways involved in Wnt and regenerative function. In ISCs, Hmga1 maintains both the stem cell pool and niche compartment whereas deregulated Hmga1 may perturb this equilibrium during carcinogenesis. Functional studies in HSCs suggest that Hmga1 also regulates self-renewal, regenerative potential, and the capacity for balanced differentiation. These findings indicate that HMGA1 is required for normal stem cell function, both during embryogenesis, and postnatally, in ASCs. Our prior work in tumor models demonstrates that a subset of HMGA1 stem cell pathways are hi-jacked by cancer cells to drive tumor progression. Together, these studies provide compelling rationale for further research to determine how to harness HMGA1 for regenerative medicine and to target it in cancer therapy. Disclosures No relevant conflicts of interest to declare.

Defining Adult Stem Cells by Function, not by Phenotype

2018 ◽  
Vol 87 (1) ◽  
pp. 1015-1027 ◽  
Author(s):  
Hans Clevers ◽  
Fiona M. Watt
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Tissue Repair ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Open Approach ◽  
Physical Entity ◽  
Hematopoietic Stem ◽  
A Cell

Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells. The nature of such a cell may be different under steady state conditions and during tissue repair. We discuss emerging examples including the renewal strategies of the skin, gut epithelium, liver, lung, and mammary gland in comparison with those of the hematopoietic system. While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues.

scholarly journals Mesenchymal stem cell properties of dental pulp cells from deciduous teeth

2011 ◽  
Vol 63 (4) ◽  
pp. 933-942 ◽  
Author(s):  
N. Nikolic ◽  
A. Krstic ◽  
D. Trivanovic ◽  
S. Mojsilovic ◽  
J. Kocic ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Dental Pulp ◽  
Adult Stem Cells ◽  
Mesenchymal Cell ◽  
Deciduous Teeth ◽  
Proliferative Potential ◽  
Stem Cell Markers ◽  
Hematopoietic Stem ◽  
Cell Markers

In the present study we have isolated and identified mesenchymal stem cells (MSCs) from the exfoliated deciduous teeth dental pulp (DP-MSCs), as plastic-adherent, spindle-shaped cells with a high proliferative potential. Immunophenotype analyses revealed that DP-MSCs were positive for mesenchymal cell markers (CD90, CD44, CD105, STRO-1, vimentin and ?-SMA), and negative for hematopoietic stem cell markers (CD11b, CD33, CD34, CD45, CD235a). DPMSCs were also capable of differentiating into adipogenic, chondrogenic, myogenic and osteogenic lineages, fulfilling the functional criterion for their characterization. These results demonstrate that DP-MSCs offer a valuable, readily accessible source to obtain and store adult stem cells for future use.

scholarly journals Epigenetic Erosion in Adult Stem Cells: Drivers and Passengers of Aging

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 237 ◽  
Author(s):  
Christian Kosan ◽  
Florian Heidel ◽  
Maren Godmann ◽  
Holger Bierhoff
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Adult Stem Cells ◽  
Healthy Aging ◽  
Cell Function ◽  
Functional Decline ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

In complex organisms, stem cells are key for tissue maintenance and regeneration. Adult stem cells replenish continuously dividing tissues of the epithelial and connective types, whereas in non-growing muscle and nervous tissues, they are mainly activated upon injury or stress. In addition to replacing deteriorated cells, adult stem cells have to prevent their exhaustion by self-renewal. There is mounting evidence that both differentiation and self-renewal are impaired upon aging, leading to tissue degeneration and functional decline. Understanding the molecular pathways that become deregulate in old stem cells is crucial to counteract aging-associated tissue impairment. In this review, we focus on the epigenetic mechanisms governing the transition between quiescent and active states, as well as the decision between self-renewal and differentiation in three different stem cell types, i.e., spermatogonial stem cells, hematopoietic stem cells, and muscle stem cells. We discuss the epigenetic events that channel stem cell fate decisions, how this epigenetic regulation is altered with age, and how this can lead to tissue dysfunction and disease. Finally, we provide short prospects of strategies to preserve stem cell function and thus promote healthy aging.

Membrane-bound SCF and VCAM-1 synergistically regulate the morphology of hematopoietic stem cells

2021 ◽  
Vol 220 (10) ◽  
Author(s):  
Jia Hao ◽  
Hao Zhou ◽  
Kristen Nemes ◽  
Daniel Yen ◽  
Winfield Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Stromal Cells ◽  
Adult Stem Cells ◽  
Nuclear Retention ◽  
Signaling Mechanism ◽  
Hematopoietic Stem ◽  
Membrane Bound ◽  
Underlying Mechanisms

Membrane-bound factors expressed by niche stromal cells constitute a unique class of localized cues and regulate the long-term functions of adult stem cells, yet little is known about the underlying mechanisms. Here, we used a supported lipid bilayer (SLB) to recapitulate the membrane-bound interactions between hematopoietic stem cells (HSCs) and niche stromal cells. HSCs cluster membrane-bound stem cell factor (mSCF) at the HSC-SLB interface. They further form a polarized morphology with aggregated mSCF under a large protrusion through a synergy with VCAM-1 on the bilayer, which drastically enhances HSC adhesion. These features are unique to mSCF and HSCs among the factors and hematopoietic populations we examined. The mSCF–VCAM-1 synergy and the polarized HSC morphology require PI3K signaling and cytoskeletal reorganization. The synergy also enhances nuclear retention of FOXO3a, a crucial factor for HSC maintenance, and minimizes its loss induced by soluble SCF. Our work thus reveals a unique role and signaling mechanism of membrane-bound factors in regulating stem cell morphology and function.

scholarly journals Anti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells

2020 ◽  
Vol 21 (10) ◽  
pp. 3497 ◽  
Author(s):  
Joung-Sun Park ◽  
Yung-Jin Kim
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Stem Cell ◽  
Adult Stem Cells ◽  
Intestinal Stem Cells ◽  
Aging Effects ◽  
Age Related ◽  
Tissue Aging ◽  
And Oxidative Stress ◽  
Age Related Changes

Age-related changes in tissue-resident adult stem cells may be closely linked to tissue aging and age-related diseases, such as cancer. β-Hydroxybutyrate is emerging as an important molecule for exhibiting the anti-aging effects of caloric restriction and fasting, which are generally considered to be beneficial for stem cell maintenance and tissue regeneration. The effects of β-hydroxybutyrate on adult stem cells remain largely unknown. Therefore, this study was undertaken to investigate whether β-hydroxybutyrate supplementation exerts beneficial effects on age-related changes in intestinal stem cells that were derived from the Drosophila midgut. Our results indicate that β-hydroxybutyrate inhibits age- and oxidative stress-induced changes in midgut intestinal stem cells, including centrosome amplification (a hallmark of cancers), hyperproliferation, and DNA damage accumulation. Additionally, β-hydroxybutyrate inhibits age- and oxidative stress-induced heterochromatin instability in enterocytes, an intestinal stem cells niche cells. Our results suggest that β-hydroxybutyrate exerts both intrinsic as well as extrinsic influence in order to maintain stem cell homeostasis.

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